This is a competing renewal of DK 51081. Prior studies in the last two funding cycles have demonstrated that human parathyroid hormone-related protein {PTHrP(1-36)}: 1) reproduces the hallmarks of humoral hypercalcemia of malignancy in humans; 2) can be safely administered to humans; 3) is identical to parathyroid hormone in terms of pharmacokinetics when administered intravenously; but, 4) is absorbed much more rapidly than PTH when administered subcutaneously; 5) increases bone mass, bone mineral density, and is an anabolic agent in oophorectomized rats; 6) markedly improves skeletal biomechanics in rats; and, most recently, 7) appears to be a pure anabolic agent for the treatment of postmenopausal osteoporosis when administered to humans. [unreadable] [unreadable] In the current application, we have four Specific Aims: [unreadable] [unreadable] 1. To determine whether PTHrP alone, i.e., without estrogen, is purely anabolic, and whether sequential PTHrP followed by a bisphosphonate is superior to a bisphosphonate alone; [unreadable] 2. To directly compare the pharmacokinetics of hPTHrP(1-36) to those of hPTH(1-34) following subcutaneous injection. [unreadable] 3. To determine the maximum safe dose, and the therapeutic window, for hPTHrP(1-36). [unreadable] 4. To determine the effect of the new maximal dose on BMD, and define at the histomorphometric level the effects of PTHrP on bone formation and resorption. [unreadable] [unreadable] We anticipate that these studies will clearly demonstrate that PTHrP(1-36) is a potent anabolic skeletal agent in humans, and that is similar to, or perhaps superior to, PTH in the treatment of osteoporosis. [unreadable] [unreadable]